The delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences--e.g., gastrointestinal irritation and the like--are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
However, many drugs are not suitable for passive transdermal drug delivery because of their size, ionic charge characteristics and hydrophilicity. One method of overcoming this limitation in order to achieve transdermal administration of such drugs is the use of electrical current to actively transport drugs into the body through intact skin. The method of the invention relates to such an administration technique, i.e., to "electrotransport" or "iontophoretic" drug delivery.
Herein the terms "electrotransport," "iontophoresis," and "iontophoretic" are used to refer to the transdermal delivery of pharmaceutically active agents by means of an applied electromotive force to an agent-containing reservoir. The agent may be delivered by electromigration, electroporation, electroosmosis or any combination thereof. Electroosmosis has also been referred to as electrohydrokinesis, electro-convection, and electrically induced osmosis. In general, electroosmosis of a species into a tissue results from the migration of solvent in which the species is contained, as a result of the application of electromotive force to the therapeutic species reservoir, i.e., solvent flow induced by electromigration of other ionic species. During the electrotransport process, certain modifications or alterations of the skin may occur such as the formation of transiently existing pores in the skin, also referred to as "electroporation." Any electrically assisted transport of species enhanced by modifications or alterations to the body surface (e.g., formation of pores in the skin) are also included in the term "electrotransport" as used herein. Thus, as used herein, the terms "electrotransport", "iontophoresis" and "iontophoretic" refer to (1) the delivery of charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or agents by the process of electroosmosis, (3) the delivery of charged or uncharged drugs by electroporation, (4) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (5) the delivery of a mixture of charged and uncharged drugs or agents by the combined processes of electromigration and electroosmosis.
Systems for delivering ionized drugs through the skin have been known for some time. British Patent Specification No. 410,009 (1934) describes an iontophoretic delivery device which overcame one of the disadvantages of the early devices, namely, the need to immobilize the patient near a source of electric current. The device was made by forming, from the electrodes and the material containing the drug to be delivered, a galvanic cell which itself produced the current necessary for iontophoretic delivery. This device allowed the patient to move around during drug delivery and thus required substantially less interference with the patient's daily activities than previous iontophoretic delivery systems.
In present electrotransport devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the drug is delivered into the body. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery, and usually to circuitry capable of controlling current passing through the device. If the ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve as the counter electrode, completing the circuit. If the ionic substance to be delivered is negatively charged, then the cathodic electrode will be the active electrode and the anodic electrode will be the counter electrode.
Existing electrotransport devices additionally require a reservoir or source of the pharmaceutically active agent which is to be delivered or introduced into the body. Such drug reservoirs are connected to the anode or the cathode of the electrotransport device to provide a fixed or renewable source of one or more desired species or agents.
The present invention is directed in part to a novel drug reservoir for use in an electrotransport system. A preferred material for electrotransport drug reservoirs is polyvinyl alcohol; however, it is well known that hydrogels formed with this polymer are unstable and undergo syneresis, i.e., exude water. This causes the gel to shrink over time with the formation of a separate surface phase, thus diminishing the shelf life of the formulation.
Prior methods for alleviating syneresis have been tried. U.S. Pat. No. 4,593,053 to Jevne et al., for example, calls for a gel composed predominantly of high molecular weight polyvinylpyrrolidone; polyvinyl alcohol is included only as minor component of the gel. However, the use of more than one type of polymer in a hydrogel formulation can have undesirable consequences. For example, nonuniform distribution of a drug within the gel may result if the drug preferentially dissolves in one of the polymers. The optical clarity of the hydrogel may also be compromised. Another approach taken to reduce or eliminate syneresis is to incorporate extraneous moisture-absorbing substances in the formulation, for example, superhygroscopic polymers, synthetic resins, high molecular weight polymeric acids and acid salts, and polyhydric alcohols. See, e.g., U.S. Pat. No. 5,346,935 to Suzuki et al., and U.S. Pat. No. 4,978,531 to Yamazaki et al. Additives and associated impurities which are ionically charged can interfere with electrotransport drug delivery. Additives can also adversely affect the drug release characteristics of the hydrogel itself.
Pharmaceutical polyvinyl alcohol hydrogels that are substantially free of other polymers have also been used in drug delivery systems. For example, an improved flowable gel matrix for transdermal release of trinitroglycerol is described in U.S. Pat. No. 4,542,013 to Keith. The matrix contains two species of polyvinyl alcohol having different molecular weights, and glycerol. The matrix is described as being "less wet" than a commercial sustained release preparation, thus improving the wearability of the transdermal device. U.S. Pat. No. 4,781,926 to Hyon & Ikeda describes a pharmaceutical polyvinyl alcohol hydrogel formulation having a high content of water for the purpose of increasing the swelling of the stratum corneum and thereby enhancing drug permeation through the skin. The gel is prepared by a freeze-thaw process which requires thawing for a period longer than 10 hours to obtain mechanically strong gels. Polyvinyl alcohol has also been used to coat implantable bioactive pellets for veterinary use; see U.S. Pat. No. 5,091,185 to Castillo et al. While these references relate to polyvinyl alcohol hydrogels in the pharmaceutical context, none address the issue of syneresis or provide a way to substantially eliminate the problem of syneresis in pharmaceutical hydrogel formulations comprised of polyvinyl alcohol gels.
To the best of applicants' knowledge, then, the invention represents the first successful attempt to address syneresis in the aforementioned context, and thus provides an important advance in the art by enabling manufacture of stable pharmaceutical hydrogels having a shelf life of at least two years.